Kaposis sarcoma associated herpesvirus (KSHV) has been linked to the development of Kaposis sarcoma, primary effusion lymphoma (PEL) and a proportion of Castlemans disease. KSHV encodes several cytokine- and chemokine-like proteins, including a homologue of interleukin-6 (IL-6). Viral (v) IL-6, produced predominantly during viral replication, exibits approximately 25% amino acid identity to human and murine IL-6, suggesting that it may be the result of viral piracy of a useful cellular gene. Through experiments in vitro and in vivo, we have characterized the biological activities of vIL-6. Mice treated with vIL-6 displayed increased hematopoiesis in the myeloid, erythroid, and megakaryocytic lineages; plasmacytosis in spleen and lymph nodes; hepatosplenomegaly; and polyclonal hypergammaglobulinemia. We determined that vIL-6 expressing fibroblasts gave rise to tumors more rapidly than did control cells, and determined that vIL-6 stimulated vascular endothelial growth factor (VEGF) expression. In additional experiments, we explored the potential role of VEGF in PEL pathogenesis. Since PEL is a lymphoma that grows predominantly in liquid form and expresses vIL-6 and VEGF, we examined whether VEGF may be required for the development of PEL effusions. Using an experimental murine model of PEL development, we found that neutralizing antibodies against human VEGF prevented the development of experimental PEL in SCID/beige mice. Thus, we have shown that vIL-6 and VEGF induced by vIL-6 may be critical to the pathogenesis of certain KSHV-associated diseases.